Leading Anticancer Immunotherapeutics to Be Assessed for Continued Use for Indications Granted Accelerate Approval


Indications for pembrolizumab, nivolumab, and atezolizumab are set for examination under the FDA’s Oncologic Drugs Advisory Committee for indications granted accelerated approval in breast, urothelial, gastric, and liver cancers.

The FDA will be holding an Oncologic Drugs Advisory Committee meeting to evaluate the status of 6 indications across breast, urothelial, gastric, and liver cancers for systemic therapy agents granted accelerated approval whose confirmatory trials did not indicate a clinical benefit to treatment.1

The public 3-day meeting to be held April 27 through 29 is part of an industry-wide evaluation of accelerated approvals in oncology. Based on the updates provided, the committee will hold a general discussion about the individual drugs and decide if each is eligible for continued approval and if additional trials will be required.

“We are committed to ensuring the integrity of the accelerated approval program, which is designed to bring safe and effective drugs to patients with unmet medical needs as quickly as possible,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic diseases in the FDA’s Center for Drug Evaluation and Research, said in a press release.“The program allows the FDA to approve a drug or biologic product intended to treat a serious or life-threatening condition based on an outcome that can be measured earlier than survival that demonstrates a meaningful advantage over available therapies. However, when confirmatory trials do not confirm clinical benefit, a reevaluation must be performed to determine if the approval should be withdrawn.”

The PD-L1 inhibitor atezolizumab (Tecentriq) will be evaluated for 2 of its indications: as combination therapy with nab-paclitaxel for the treatment of adults with unresectable locally advanced or metastatic triple-negative breast cancer with tumor PD-L1 expression, which was originally granted in 2019 based on the progression-free survival and objective response rate (ORR) data from the phase 3 IMpassion130 trial (NCT02425891)2; and as treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy, an indication that was originally handed down in 2016 based on ORR results of a single-arm trial.3

Results from the IMpassion130 trial published in Lancet Oncology in 2020 failed to show a statistically significant survival advantage in the intention-to-treat population (HR, 0.86; 95% CI, 0.72-1.02; P = .078).4 In urothelial cancer, the FDA limited the use of atezolizumab in 2018 from its original indication, which was for patients with disease progression during or following platinum-containing chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This decision was based on decreased survival associated with monotherapy administration of atezolizumab.5

Two PD-1 inhibitors, pembrolizumab (Keytruda) and nivolumab (Opdivo), will also be evaluated for their indications granted as accelerated approvals.

Pembrolizumab was granted an indication for urothelial carcinoma in 2017 based on promising results observed in the phase 2 KEYNOTE-052 trial (NCT02335424).6 Similar to atezolizumab, the FDA limited this indication for pembrolizumab from its originally intended indication based on decreased survival.5 Currently, the indication under evaluation is for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.

A second indication for pembrolizumab in the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with tumors positive for PD-L1 expression and disease progression on or after 2 or more prior lines of therapy including chemotherapy and HER2-targeted therapy, if appropriate, will be looked at. This indication was original granted based on ORR results from the KEYNOTE-059 (NCT02335411).7

For hepatocellular carcinoma, both pembrolizumab and nivolumab were granted accelerated approvals for therapy following sorafenib (Nexavar) based on phase 2 trials.8,9 Since then, both agents have failed to show overall survival benefit in confirmatory trials.10,11

“This public meeting of the advisory committee creates an opportunity for external oncology experts and patients with cancer to share input and perspective with the FDA,” said Pazdur. “After this advisory meeting, our staff will consider the committee’s comments and will make final decisions regarding continuing approval of each indication.”


1. FDA In Brief: FDA Oncologic Drugs Advisory Committee to Review Status of Six Indications Granted Accelerated Approval. FDA. March 12, 2021. Accessed March 12, 2021. https://www.fda.gov/news-events/fda-brief/fda-brief-fda-oncologic-drugs-advisory-committee-review-status-six-indications-granted-accelerated

2. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer. FDA. March 8, 2019. Accessed March 12, 2021. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-pd-l1-positive-unresectable-locally-advanced-or-metastatic-triple-negative

3. Atezolizumab for urothelial carcinoma. FDA. May 18, 2016. Accessed March 12, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/atezolizumab-urothelial-carcinoma

4. Schmid P, Rugo HS, Adams S, et al; IMpassion130 Investigators. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21(1):44-59. doi: 10.1016/S1470-2045(19)30689-8

5. FDA limits the use of Tecentriq and Keytruda for some urothelial cancer patients. FDA. July 5, 2018. Accessed March 12, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-limits-use-tecentriq-and-keytruda-some-urothelial-cancer-patients

6. Pembrolizumab (Keytruda): Advanced or Metastatic Urothelial Carcinoma. FDA. May 18, 2017. Accessed March 12, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/pembrolizumab-keytruda-advanced-or-metastatic-urothelial-carcinoma

7. FDA grants accelerated approval to pembrolizumab for advanced gastric cancer. FDA. September 22, 2017. Accessed March 12, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-advanced-gastric-cancer

8. FDA grants accelerated approval to pembrolizumab for hepatocellular carcinoma. FDA. November 9, 2018. Accessed March 12, 2021. https://www.fda.gov/drugs/fda-grants-accelerated-approval-pembrolizumab-hepatocellular-carcinoma

9. FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib. FDA. September 22, 2017. Accessed March 12, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-hcc-previously-treated-sorafenib

10. Bristol-Myers Squibb Announces Results from CheckMate-459 Study Evaluating Opdivo (nivolumab) as a First-Line Treatment for Patients with Unresectable Hepatocellular Carcinoma. News release. Bristol-Myers Squibb. June 24, 2019. Accessed March 12, 2021. https://bit.ly/2x70MSX.

11. Merck Provides Update on KEYNOTE-240, a Phase 3 Study of KEYTRUDA® (pembrolizumab) in Previously Treated Patients with Advanced Hepatocellular Carcinoma. News release. Merck. February 20, 2019. Accessed March 12, 2021.https://bit.ly/2SQ6J45.

Related Videos
Thomas Marron, MD, PhD
PD-1 protein bound to PD-L1
Related Content